The invention concerns an analytical system for monitoring a substance to be analyzed (analyte) which is present in the blood of a patient.
The concentration of analytes in blood in many cases must be monitored regularly. This is especially the case when regular drug treatment is required in relation to the concentration of the particular substance. The most important example is diabetes-mellitus. Patients with this disease should constantly monitor their blood-sugar level to match their insulin injections to their need at the time and thereby to keep their blood-sugar levels (that is, the glucose concentration in blood) within specified limits. Exceeding such limits upward (hyperglycemia) or dropping below them (hypoglycemia) should be avoided with as much reliability as possible to prevent both critical acute conditions and grave long-term disabilities (for instance loss of eyesight).
The present invention in particular relates to monitoring the blood-glucose concentration though it is also applicable to other substances requiring analysis. No limitation on the general applicability of the invention is to be construed from any discussion hereafter relating to glucose determination.
Conventional analytical systems for monitoring blood-glucose concentration are composed of solid-state analysis-elements also called test carriers and an evaluation instrument. As a rule the analysis-elements and the evaluation instrument are specifically mutually matched and are provided as one system from the same manufacturer.
The analysis-elements contain reagents. When the elements are brought into contact with the test sample, the reaction between the analyte in the sample and the reagents causes a physically measurable change correlated to the concentration of said substance, in the analysis element. The evaluation instrument contains a measurement system measuring the said change and electronics to determine the concentration of the analyte on the basis of the measurement value obtained when measuring said change. Modern devices make use of microprocessors for the evaluating electronics, making possible software-controlled digital processing of the measurement values into signals corresponding to the concentration of the substance being analyzed. As a rule these analytical data are displayed in units of concentration on an alphanumeric display. However the expression "analytical data" in the sense of the invention also covers electrical signals representing the analytical results in other ways, for instance as signals to control offset displays of information relating to the concentration of the analyte such as "ideal range", "upper standard range", "upper danger zone", etc.
Different kinds of analysis-elements are known that involve different physico-chemical principles regarding the principles of reaction and the measurable change correlated to concentration. Conventional analysis systems are foremost photometric or electrochemical.
As regards photometric analytical systems, the analysis-elements contain a system of reagents. The reaction thereof with the analyte causes a photometrically detectable change (color change). In general the reagents are present in a porous-plastic or paper matrix forming a test zone of the analyzing element, the color of said matrix changing as a function of concentration. This color change can be quantitatively determined using reflection photometry.
Electrochemical analysis-elements contain a system of electrochemical reagents. The reaction thereof with the analyte affects the electrical potential across two terminals of the analysis-elements and/or the current level between two terminals of the analyzing element when the voltage across said terminals is fixed. In this case therefore the changing physically measurable quantity is the voltage or the current and is determined by a corresponding voltage or current sensor integrated into the instrument. The change of said measurement value correlating to the concentration of the analyzed substance is converted, preferably again using microprocessor evaluation electronics, into analytical data (concentration of analyzed substance).
Analytical systems operating by means of reagent containing analysis-elements (hereinafter referred to as "element-analysis systems" have become highly accurate and are handled easily enough that the patient himself/herself may use them for constant monitoring of the blood-glucose concentration (home monitoring). However they entail the significant drawback that each particular analysis requires withdrawing a drop of blood which then is placed in contact with an analysis-element. As a rule this procedure is implemented by piercing the finger, in other words, each analysis entails painful skin injury with some danger of infection. Such a procedure is called "invasive analysis".
In order to allow continuous monitoring of the concentration of a substance to be analyzed in blood while providing good accuracy and a lesser number of invasive interventions to secure samples, the invention, based on an analytical system of the type discussed before, discloses a system which includes a sensor unit portable on the patient body and comprising a sensor which, free of reagents, directly measures at the patient body a parameter correlating with the concentration of the analyzed substance, said unit further comprising a transmitter to wirelessly transmit data signals. Said system furthermore includes sensor evaluation electronics to determine sensor-analysis data from the sensor measurement values of the measured parameter. The evaluation instrument is the central unit of an integrated analysis-element/sensor monitoring-system and includes a wireless receiver to receive the data signals from the sensor unit, further calibrating means to calibrate the sensor-analysis data on the basis of the analytical data from the analysis-element ("element analysis data") and a data memory for the long-term storage of analytical data.
Reagent-free, sensor-analysis systems for determining blood analytes have been described in various embodiments. For some substances to be analyzed (especially the blood oxygenation values and the blood gas concentrations) such systems have become practically significant. However for a number of other substances to be analyzed, in particular glucose, they have not been adequately practical.
A survey of non-invasive methods to determine glucose is given in "PHYSICOCHEMICAL DETERMINATION OF GLUCOSE IN VIVO" by J. D. Kruse-Jarres, J. Clin. Chem. Clin. Biochem. 26, 1988, pp 201-8.
Foremost the invention concerns systems employing the interaction between irradiated light and the tissue of a living human (preferably the dermal tissue) for the purpose of analytically determining the concentration of an analyte therein. It is assumed that the concentration of the analyte in the (blood-circulating) tissue correlates adequately for practical purposes with the corresponding concentration in the blood. In such systems the sensor unit includes a light emitter irradiating the tissue. Furthermore a light detector is present by means of which, following its interaction with the tissue, light leaving the body part is sensed in order to determine a measurable physical light property which changes by interaction with the tissue. In such methods, this measurable physical property forms a parameter which correlates with the concentration of the analyzed substance.
Most methods of this kind known so-far are based on spectroscopic analysis. The characteristic absorption (caused by the vibrational and rotational states of the molecules of the analyzed substance) is determined therein by ascertaining the dependence of optical absorption on the light wavelength. In practice typically light of different wavelengths from a narrow-band light emitter is irradiated and the light received by the light detector is then measured. Alternatively the irradiation may be from a broad-band light emitter and a wavelength-selective measurement may then be carried out at the detection side. The absorption bands of the molecules under discussion (in particular of glucose) are far into the infrared range of light. However, tissue water causing strong optical absorption in this range, most authors suggest measurement wavelengths in the near infrared, whereby harmonics of the molecular oscillatory and rotational states may be detected. Illustrative such systems are described in EP-A0 160 768, in WO 93/00856 and in U.S. Pat. No. 5,028,787.
In an especially preferred embodiment of the invention, a sensor system is used wherein a light parameter is determined that depends on the tissue's index of refraction. This method is substantially based on the finding that the change in index of refraction of the liquid in the tissue relating to the glucose concentration may be used as the parameter correlated to the glucose concentration.
For the implementation of this method a measurement-technique has been suggested in which signals are determined which are affected by the multi-scattering of light by scattering centers in the tissue. Such a procedure is described in the international patent application PCT/DE 93/01058. Under the conditions of measurement described in said publication, multi-scattering causes enhancement of the effect tied to the change in index of refraction, and said enhancement can be ascertained as a comparatively strong and hence well measurable signal change. The cited reference contains further details which are incorporated by reference into the present disclosure.
German patent application 43 37 570 describes analysis of glucose based on the determination of a light parameter corresponding to the light transit time in the tissue. Such a transit time parameter may be directly the time of travel of an exceedingly short light pulse. However it is much simpler to ascertain instead the phaseshift of light within the tissue as a transit-time parameter which correlates with the tissue glucose concentration.
Lastly the simultaneously filed German patent application 44 15 728 "METHOD AND DEVICE FOR ANALYZING GLUCOSE IN A BIOLOGICAL SAMPLE" describes how to determine changes in tissue index-of-refraction using low-coherence interferometry. Such determination may take place directly by ascertaining the light's optical path in the tissue or indirectly in such manner that the light scattering coefficient in the tissue is being ascertained. The scattering coefficient is affected decisively by the relation between the index of refraction of the liquid and that of the tissue scattering centers (for instance cells). Again the contents of said application is incorporated by reference into the present disclosure.